Vitamin D is a class of compounds with polyene structure, with important physiological activity. The common vitamin D3 may be hydroxylated to 25-hydroxy vitamin D3 [25-(OH)D3] under the action of 25-hydroxylase in the liver cell mitochondria, and then be hydroxylated into 1,25-(OH)2D3 and 24,25-(OH)2D3 by the kidney. 1,25-(OH)2D3 or Calcitriol, a bioactive type of vitamin D3, plays an important role in maintaining calcium and phosphorus metabolism balance and bone mineralization, and is used clinically for the treatment of renal osteodystrophy, parathyroid dysfunction, anti-vitamin D rickets and so on. During the clinical treatment of these lesions, the vitamin D analogues were have been found effective for the treatment of psoriasis, but easy to lead to hypercalcemia as side effect, which limits the application.
There are currently three types of vitamin D3 analogues for the treatment of psoriasis: Calcitriol, Tacalcitol and Calcipotrol. No clear research results about their adverse effects on serum calcium have been found yet. So the development of new vitamin D compounds with better efficacy, less side effect of hypercalcemia and more clinical value in the treatment of psoriasis, will be a very meaningful work.
Pefcalcitol, a fluoroamide analogue, is a new compound developed by Chugai Corporation of Japan. Pefcalcitol has similar structure with Maxacalcitol and Calcitriol, with affinity for vitamin D receptors of 34%, 20% and 100%, respectively, but its in-vivo stability is 14 times than that of Maxacalcitol, and the antiproliferative activity is 12 times than that of Maxacalcitol and the calcium-related activity is only 17% of Maxacalcitol. These properties make Pefcalcitol a candidate compound for psoriasis with a higher selective therapeutic potential. The development of clean and efficient Pefcalcitol production process to meet the potential needs of clinical medication has significant economic and social effects.
In the prior art, the preparation of Pefcalcitol mainly has the following two routes:
(1) WO2001/96293 first reported the synthetic route of Pefcalcitol:
a basic molecular skeleton was constructed through a steroid, and then the ring thereof was opened under illumination to obtain the product, the specific synthetic route is as follows:

In the above method, the original inventor constructed a basic molecular skeleton through a steroid, and then the ring of which was opened under illumination to obtain the polyene compound 1, and finally obtained Pefcalcitol and the like. (See the literature Bioorganic & Medicinal Chemistry Letters 16 (2006) 3323-3329.).
The route is simple and short, but the yield of the key step of steroid ring-opening is very low, generally only 30-40%. This synthetic method uses the steroid reaction to construct a basic molecular skeleton first, but the steroid reaction needs to be fermented, as a result that the engineering control is difficult and the product quality is not high. Besides, the ring needs to be opened under illumination to obtain the product after obtaining the basic molecular skeleton in this synthesis method, but the illumination reaction requires the use of special reaction device, which has many control points, harsh process requirement, small reaction capacity and difficult impurity purification, and is not conducive to large-scale preparation of products.
In summary, the route is short, but has harsh requirements for the reaction device and conditions, which is difficult to achieve scale production; both the reaction conversion rate and the yield are low, and the cost is high; the steroid reaction and illumination ring-opening reaction are difficult to control, the purification of the impurity caused by illumination is difficult, making it difficult to achieve large-scale rapid preparation, therefore it is not appropriate to enlarge production.
(2) Chugai researchers in Japan applied for a patent route in 2006: EP1955999A1, the patent application designed a palladium-catalyzed total synthesis process, and reported that the target molecule was constructed through an allyl bromine intermediate and an enyne intermediate under the action of a palladium catalyst. This is an effective method for the total synthesis of vitamin D analogue. The specific synthetic route is as follows:

In the above method, the original inventor constructed the target molecule through an allyl bromide intermediate 3 and an enyne intermediate 4 under the action of a palladium catalyst, which is an effective method for the total synthesis of the vitamin D analogue. But the yield of the trost reaction itself is not high, only 58.3%, meanwhile the reaction conditions are harsh, special equipment is required, raw materials are more expensive, post-processing is cumbersome, the total yield of the route is only 43.7%. Therefore, it is not appropriate to enlarge production. In addition, catalyst involved reaction process is prone to produce elimination, rearrangement and other by-products; the use of precious metal catalyst palladium increases the cost, and affects the quality of the final product as well, the heavy metal residue limit needs to be strictly controlled in accordance with the requirements of ICH quality research, which will increase the difficulty of the process.
In summary, neither the route in which a basic molecular skeleton is constructed through the steroid first, and then the ring is opened under the illumination to obtain the product, nor the route in which the target molecule is constructed through an allyl bromine intermediate and an enyne intermediate under the action of a palladium catalyst, can obtain Pefcalcitol ideally. Accordingly, there is a strong need in the art for a new preparation method of Pefcalcitol to solve the above technical problems.